title: New potential therapeutic approach for the treatment of B-Cell malignancies using chlorambucil/hydroxychloroquine-loaded anti-CD20 nanoparticles.
abstract: Current B-cell disorder treatments take advantage of dose-intensive chemotherapy regimens and immunotherapy via use of monoclonal antibodies. Unfortunately, they may lead to insufficient tumor distribution of therapeutic agents, and often cause adverse effects on patients. In this contribution, we propose a novel therapeutic approach in which relatively high doses of Hydroxychloroquine and Chlorambucil were loaded into biodegradable nanoparticles coated with an anti-CD20 antibody. We demonstrate their ability to effectively target and internalize in tumor B-cells. Moreover, these nanoparticles were able to kill not only p53 mutated/deleted lymphoma cell lines expressing a low amount of CD20, but also circulating primary cells purified from chronic lymphocitic leukemia patients. Their safety was demonstrated in healthy mice, and their therapeutic effects in a new model of Burkitt's lymphoma. The latter serves as a prototype of an aggressive lympho-proliferative disease. In vitro and in vivo data showed the ability of anti-CD20 nanoparticles loaded with Hydroxychloroquine and Chlorambucil to increase tumor cell killing in comparison to free cytotoxic agents or Rituximab. These results shed light on the potential of anti-CD20 nanoparticles carrying Hydroxychloroquine and Chlorambucil for controlling a disseminated model of aggressive lymphoma, and lend credence to the idea of adopting this therapeutic approach for the treatment of B-cell disorders.
authors.affiliation: Dept. of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: Nelly
authors.initials: N
authors.lastname: Mezzaroba
authors.forename: Sonia
authors.initials: S
authors.lastname: Zorzet
authors.forename: Erika
authors.initials: E
authors.lastname: Secco
authors.forename: Stefania
authors.initials: S
authors.lastname: Biffi
authors.forename: Claudio
authors.initials: C
authors.lastname: Tripodo
authors.forename: Marco
authors.initials: M
authors.lastname: Calvaruso
authors.forename: Ramiro
authors.initials: R
authors.lastname: Mendoza-Maldonado
authors.forename: Sara
authors.initials: S
authors.lastname: Capolla
authors.forename: Marilena
authors.initials: M
authors.lastname: Granzotto
authors.forename: Ruben
authors.initials: R
authors.lastname: Spretz
authors.forename: Gustavo
authors.initials: G
authors.lastname: Larsen
authors.forename: Sandra
authors.initials: S
authors.lastname: Noriega
authors.forename: Marianna
authors.initials: M
authors.lastname: Lucafò
authors.forename: Eduardo
authors.initials: E
authors.lastname: Mansilla
authors.forename: Chiara
authors.initials: C
authors.lastname: Garrovo
authors.forename: Gustavo H
authors.initials: GH
authors.lastname: Marín
authors.forename: Gabriele
authors.initials: G
authors.lastname: Baj
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pozzato
authors.forename: Luis
authors.initials: L
authors.lastname: Núñez
authors.forename: Paolo
authors.initials: P
authors.lastname: Macor
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D018951:Antigens, CD20 / Q000276:immunology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002699:Chlorambucil / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004338:Drug Combinations; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D005434:Flow Cytometry; D006886:Hydroxychloroquine / Q000494:pharmacology* / Q000627:therapeutic use; D007150:Immunohistochemistry; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000627:therapeutic use*; D000069283:Rituximab
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D004338:Drug Combinations; D002699:Chlorambucil; D000069283:Rituximab; D006886:Hydroxychloroquine